1. Field of the Invention
The present invention relates to new methods and new preparations for preventing adhesions to body organs and/or parts of body organs.
2. Brief Description of the Background Art
After invasive therapeutic intervention or in the course of a disease, adhesions to body organs and/or parts of body organs may result in life-threatening situations. The formation of adhesions is also observed after surgical intervention in the thoracic cavities or in the abdominal cavity. In spite of greater efforts to prevent such adhesions, no satisfactory method of treatment has been discovered thus far.
The role of fibrin formation in the formation of adhesions can be explained as follows: after invasive therapeutic treatment or in inflammatory reactions, plasma proteins as well as fibrinogen and other coagulation proteins are released from the tissue. Fibrinogen is deposited in the form of fibrin. The fibrin network which forms then connects (attaches) adjacent surfaces of organs or other parts of organs. If the fibrin is not dissolved, dense adhesions are formed which may result, for example, in dangerous constrictions of the intestine. Fibrin adhesions which have been freshly formed are gradually surrounded by fibroblasts to form permanent tissue connections.
The degree of possible spontaneous fibrinolysis depends on the release of tissue plasminogen activator (t-PA) from the vascular endothelium, but also from mesothelial cells such as those which occur in the abdominal cavity. After a peritoneal intervention, however, there is a reduction in the fibrinolytic activity in these mesothelial cells. If fibrinolysis is consequently incomplete, the fibrin residues behave like centers into which fibroblasts grow. Capillaries are then formed which give rise to fibrin adhesion which are later replaced by collagen-containing adhesions, the collagen being synthesized by the fibroblasts.
To prevent the formation of post-operative or inflammation-induced adhesions, the systemic administration of ibuprofen has been proposed (U.S. Pat. No. 4,346,108); other proposals concern the parenteral administration of antihistamines, corticosteroids and antibiotics or the intraperitoneal administration of dextran solutions or polyvinylpyrrolidone solutions. The appropriate use of streptokinase, streptodornase and urokinase has also been proposed. Ascherl et al., Medwelt 34 (13):410-415 (1983); Mund-Hoym et al., Geburtsb. u. Frauenheilkunde 44:463-467 (1984); Minju et al., Acta Academiae Medicinae Wuhan 3(2):77-83 (1983)
Human fibrinolysin has also been investigated on its own and in conjunction with other drugs for its ability to suppress post-operative adhesions. Gazzaniga et al., Arch. Surg. 110:429-432 (1975) Several investigators have concluded that the post-operative formation of adhesions in the abdominal cavity is connected with a traumatically or ischaemically induced reduction in the activity of the plasminogen activator. Holtz, The Journal of Reproductive Medicine (4):141-146 (1980), Rivkind et al., Eur. Surg. Res. (Switzerland) (17)4:254-258 (1985) and Buckman et al,, Journal of Surgical Research 20(1):1-5 (1976).
The direct topical application of tissue plasminogen activator (t-PA) to prevent post-operative intraperitoneal adhesions was described in European Patent Application No. 0.227.400. t-PA, which occurs in the body both as a single-stranded and as a double-stranded molecule, has a high affinity for fibrin which forms clots. Natural t-PA is glycosylated and contains fatty acid residues. All these types of t-PA have a specific affinity for fibrin and at tile same time activate plasminogen to form plasmin. Plasmin effects the proteolytic breakdown of fibrin. Since fibrin is pathophysiologicatly responsible for the formation of adhesions, t-PA results in the prevention of adhesion formation and, in some cases, in the removal of adhesions already formed, e.g. in the abdominal cavity after surgical intervention or after inflammatory processes. The t-PA used is isolated from human tissue or obtained using recombinant DNA technology (GB 2.119.804 A, EP-A-0.174.835 and 0.100.982).
According to European Patent Application No. 0 227 400 mentioned above, t-PA is applied topically, for example, in the area of surgical intervention, immediately after surgery has ended if possible or before the wound has started to heal, in order to prevent adhesion of sections of tissue and/or organs. In the case of inflammatory processes, t-PA is applied to the affected areas and, if necessary, a t-PA preparation is additionally applied slowly through a catheter which ends at the site of intervention.
Sterile t-PA preparations containing a pharmaceutically acceptable carrier, e.g., a phosphate-buffered saline solution, an isotonic saline solution or purified water have also been described. Suitable organic carriers include lipids, e.g. phosphorus lipid micelles or vesicles and also dextran, polymers such as p-dioxanones, lactides and/or glycolides in the form of adsorbable polymers which are microencapsulated or embedded in ointment bases or occur in an aqueous solution of a surfactant substance, e.g., a polyoxyethylene/polyoxypropylene block copolymer or a sorbitan fatty acid ester/polyoxyethylene ether. The preferred preparations are those in which t-PA is contained in a carrier with delayed release of the active substance, which releases the active substance in controlled manner within a period from 1 to 7 days. Examples of carriers with delayed, controlled release of active substance include adsorbent polymers which occur as microcapsules or are present in an ointment base, but more particularly phospholipid vesicles, i.e., liposomes.